Advanced squamous cell carcinoma of the head and neck or esophagus have a very poor five-year survival despite aggressive local treatment with surgery, radiotherapy or both. Many such patients die of metastatic disease. Therefore, a pilot trial of aggressive combination chemotherapy was warranted to determine if an improved response rate or survival can be obtained. Bleomycin, cis-platinum II with hydration, and high-dose methotrexate with citrovorum rescue are agents with activity in these tumors. Thirty-three patients were treated with combinations of these agents. Twenty-six received a three-drug combination and 7 patients received only DDP and bleomycin. There was a 73% response rate in previously untreated patients with 4 complete and 12 partial responses, and a 55% response rate in previously treated patients, all PR's. Duration of response to a single course of chemotherapy is 8-12 weeks. Toxicity included vomiting, alopecia, leukopenia, thrombocytopenia, mucositis and elevated serum creatinine. There were 2 drug-related deaths. Among the 22 responders, 12 had surgery, 5 had subsequent radiotherapy. Among the 11 failures to therapy, 3 had surgery and 1 had radiotherapy. Twelve patients received no local therapy. Similar studies are now underway in cooperative groups.